Gonorrhea is a common sexually transmitted infection woridwide. Women usually have few or no symptoms associated with infection, which often leads to delays in treatment and the development of complications such as pelvic inflammatory disease and infertility and increased likelihood of acquiring HIV infection. A better understanding of the innate immune response to this pathogen will lead to treatments that can lessen the infectious complications and support the development of protective vaccine strategies. We have developed two peptide mimics of conserved gonococcal lipooligosaccharide (LOS) derived oligosaccharides as potential experimental vaccine candidates. One, called 207, is displayed by 95% of gonococci in vivo; the second, called 2-1-L8, identifies an additional 3% of gonococci. Gonorrhea elicits an indiscriminate Th2 immune response in humans that results in antibodies that in the aggregate posses ill-defined function, resulting in failure of protective immunity against subsequent bouts of infection. 207 and 2-1-L8 antibodies and, in addition, antibodies against reduction modifiable protein (Rmp) are among the respondents to infection. Human 2C7 and 2-1-L8 antibodies exert complement (C) dependent killing; Rmp antibodies subvert (or block) C dependent killing and contribute to increased susceptibility to gonococcal infection. In Specific Aim 1, we hypothesize that a favorable ratio of 2C7+ 2-1-L8 antibodies H- Rmp antibodies is necessary to prevent infection after exposure. We will determine the ratio of 2C7+ 2-1-L8 antibodies ^ Rmp antibodies in the one-third of women who withstand infection after recent exposure. Gonococci bind directly to the human C regulators, 04 binding protein (C4BP), a classical C pathway regulator and Factor H, an alternative C pathway regulator, which interfere with numerous C dependent functions that kill gonococci. Specificity of C regulator binding is unique to humans; other animal species do not bind their own C regulators, which results in routine killing of gonococci by non-human C. In Specific Aim 2, we will adapt the mouse experimental model of gonococcal infection by testing the efficacy of 2C7 and 2-1-L8 peptide mimic vaccination in human transgenic mice that express human C4BP, factor H or both. We hypothesize that gonococcal infection will be enhanced in human C regulator transgenic mice, but that vaccine elicited immune antibodies, which overcome human regulator effects, will prevent or limit infection. In Specific Aim 3, we will refine the vaccine model further by including Rmp antibodies as part of the antibody repertoire in vaccinated mice to test susceptibility to gonococcal infection in these mice, thereby simulating the human condition where sufficient bactericidal antibody titers can overcome the blocking antibody effect.